Apparatus for adjunct (add-on) therapy of Dementia and Alzheimer&#39;s disease utilizing an implantable lead and an external stimulator

ABSTRACT

An apparatus and method for adjunct (add-on) therapy for dementia and Alzheimer&#39;s disease comprises an implanted lead-receiver, and an external stimulator. The implanted lead receiver comprises a secondary coil and at least one electrode in contact with a cranial nerve. The external stimulator comprises circuitry, at least two pre-determined programs, power source and a primary coil. The stimulator and the lead-receiver are inductively coupled. The external stimulator emits pulsed electrical signals according to predetermined programs for afferant vagal nerve stimulation.

This application is a division of application Ser. No. 09/178,057 filedOct. 26, 1998 now U.S. Pat. No. 6,269,270.

FIELD OF INVENTION

This invention relates generally to non-pharmacologic adjunct (add-on)treatment for Dementia, more specifically to adjunct treatment ofDementia including Alzheimer's disease by modulating electrical signalsto a selected nerve or nerve bundle utilizing an easily implantedlead-receiver and an external stimulator.

BACKGROUND

There is mounting scientific evidence that electrical stimulation hasbeneficial therapeutic effects for patients with Dementia and probableAlzheimer's disease. Most of the scientific studies are performedutilizing the technique of transcutaneous electrical nerve stimulation(TENS). In the TENS method (such as a device manufactured by XytronMedical), two standard carbon rubber electrodes with gel are fixed onpatient's skin across the tissue to be stimulated, one electrode beingthe negative pole and other being the positive pole. Utilizing the twoelectrodes, asymmetric biphasic pulses are used for stimulation withvarying frequency and pulse widths. Because the skin has high impedance,relatively large outputs are required to stimulate, and the site to bestimulated is not very specific. Other tissues including muscle, betweenthe two skin electrodes will be stimulated.

Another method of stimulating nerve is to use a percutaneous needle, ora lead with one end (distal end) being next to the nerve and utilizing apatch somewhere on the skin as the return electrode. Such a method isnot feasible for long term stimulation because of the potential forinfection, but can be useful for short term testing.

Two recent studies reported by Scherder et al., using TENS as the methodof stimulation, described the benefits on memory and affective behaviorin patients with probable Alzheimer's disease. There was a partialdisappearance of the treatment effects on memory and affective behaviorafter a treatment-free period of 6 weeks, suggesting that continuationof the stimulation is necessary for maintaining or even furtherimproving the treatment effects.

The rationale underlying the TENS study was that peripheral nervestimulation would activate the hippocampus and hypothalamus structureswhich are affected in Alzheimer's disease (AD). This assumption is basedupon animal experimental studies in which hippocampal activity was foundto increase after peripheral tactile stimulation and the activity of thehypothalamus was enhanced by electro-acupuncture, a type of peripheralelectrical stimulation. The hippocampus is highly involved in memoryprocesses, in close association with other brain regions such as theinferomedial temporal cortex and the ventromedial prefrontal cortex. Thehypothalamus plays a crucial role in affective behavior in Alzheimer'sdisease.

Most nerves in the human body are composed of thousands of fibers, ofdifferent sizes designated by groups A, B and C, which carry signals toand from the brain. The vagus nerve, for example, may have approximately100,000 fibers of the three different types, each carrying signals. Eachaxon (fiber) of that nerve conducts only in one direction, in normalcircumstances. The A and B fibers are myelinated (i.e., have a myelinsheath, constituting a substance largely composed of fat), whereas the Cfibers are unmyelinated.

A commonly used nomenclature for peripheral nerve fibers, using Romanand Greek letters, is given in the table below,

External Conduction Diameter Velocity Group (μm) (m/sec) MyelinatedFibers Aα or IA 12-20  70-120 Aβ: IB 10-15 60-80 II  5-15 30-80 Aγ 3-815-40 Aδ or III 3-8 10-30 B 1-3  5-15 Unmyelinted fibers C or IV 0.2-1.50.5-2.5

The diameters of group A and group B fibers include the thicknesses ofthe myelin sheaths. Group A is further subdivided into alpha, beta,gamma, and delta fibers in decreasing order of size. There is someoverlapping of the diameters of the A, B, and C groups becausephysiological properties, especially the form of the action potential,are taken into consideration when defining the groups. The smallestfibers (group C) are unmyelinated and have the slowest conduction rate,whereas the myelinted fibers of group B and group A exhibit rates ofconduction that progressively increase with diameter. Group B fibers arenot present in the nerves of the limbs, they occur in white rami andsome cranial nerves. Myelinated fibers also have very low stimulationthresholds compared to the unmyelinated type, and exhibit a particularstrength-duration curve or respond to a specific pulse width versusamplitude for stimulation. The A and B fibers can be stimulated withrelatively narrow pulse widths, from 50 to 200 microseconds (μs), forexample. The A fiber conducts slightly faster than the B fiber and has aslightly lower threshold. The C fibers are very small, conductelectrical signals very slowly, and have high stimulation thresholdstypically requiring a wider pulse width (300-1,000 μs) and a higheramplitude for activation. Selective stimulation of only A and B fibersis readily accomplished. The requirement of a larger and wider pulse tostimulate the C fibers, however, makes selective stimulation of only Cfibers, to the exclusion of the A and B fibers, virtually, unachievableinasmuch as the large signal will tend to activate the A and B fibers tosome extent as well.

A-Beta fibers respond very well to high frequency stimulation, e.g., 100Hz with an intensity just above threshold. In a recent study, A-Betafibers also appeared to respond to low-frequency stimulation (2 Hz) witha higher intensity. Activation of A-Delta and C fibers is usually causedby low-frequency stimulation (less than 10 Hz) with higher intensity. Toactivate all three types of afferent nerve fibers, high-frequency andlow-frequency stimulation can be combined in one treatment.

The vagus nerve is composed of somatic and visceral afferents (i.e.,inward conducting nerve fibers which convey impulses toward the brain)and efferents (i.e., outward conducting nerve fibers which conveyimpulses to an effector). Usually, nerve stimulation activates signalsin both directions (bi-directionally). It is possible, however, throughthe use of special electrodes and waveforms, to selectively stimulate anerve in one direction only (unidirectionally). The vast majority ofvagal nerve fibers are C fibers, and a majority are visceral afferentshaving cell bodies lying in masses or ganglia in the skull. The centralprojections terminate largely in the nucleus of the solitary tract whichsends fibers to various regions of the brain, e.g., the hypothalamus,hippocampus, and amygdala. See FIG. 1A (from: Epilepsia, vol. 31, suppl.2: 1990, page S2).

An activation of higher-level areas, e.g. the hippocampus andhypothalamus, by TENS or cranial nerve (such as vagal nerve) stimulationmight be transmitted by afferent nerve fibers, i.e. thick-myelinatedA-Beta fibers, thin-myelinated A-Delta fibers, and Unmyelinated Cfibers. The basic premise of vagal nerve stimulation is that vagalvisceral afferents have a diffuse central nervous system (CNS)projection, and activation of these pathways has a widespread effect onneuronal excitability.

Observations on the profound effect of electrical stimulation of thevagus nerve on central nervous system (CNS) activity, extends back to1930's. Intermittent vagal stimulation has been relatively safe and welltolerated. The minimal side effects of tingling sensations and briefvoice abnormalities have not been distressing. The vagus nerve providesan easily accessible, peripheral route to modulate central nervoussystem (CNS) function. Other cranial nerves can be used for the samepurpose, but the vagus nerve is preferred because of its easyaccessibility. In the human body there are two vagal nerves (VN), theright VN and the left VN. Each vagus nerve is encased in the carotidsheath along with the carotid artery and jugular vein. The innervationof the right and left vagal nerves is different. The innervation of theright vagus nerve is such that stimulating it results in profoundbradycardia (slowing of the heart rate). The left vagal nerve has someinnervation to the heart, but mostly innervates the visceral organs suchas the gastrointestinal tract. It is known that stimulation of the leftvagal nerve does not cause any significant deleterious side effects.

The cervical component of the vagus nerve (10^(th) cranial nerve)transmits primarily sensory information that is important in theregulation of autonomic activity by the parasympathetic system. Generalvisceral afferents constitute approximately 80% of the fibers of thenerve, and thus it is not surprising that vagal stimulation (VS) canprofoundly affect CNS activity. With cell bodies in the nodose ganglion,these afferents originate from receptors in the heart, aorta, lungs, andgastrointestinal system and project primarily to the nucleus of thesolitary tract which extends throughout the length of the medullaoblongata.

PRIOR ART

U.S. Pat. No. 3,796,221 (Hagfors) is directed to controlling theamplitude, duration and frequency of electrical stimulation applied froman externally located transmitter to an implanted receiver byinductively coupling. Electrical circuitry is schematically illustratedfor compensating for the variability in the amplitude of the electricalsignal available to the receiver because of the shifting of the relativepositions of the transmitter-receiver pair. By highlighting thedifficulty of delivering consistent pulses, this patent points away fromapplications such as the current application, where consistent therapymay need to be continuously sustained over a prolonged period of time.The methodology disclosed is focused on circuitry within the receiver,which would not be sufficient when the transmitting coil and receivingcoil assume significantly different orientation, which is likely in thecurrent application. The present invention discloses a novel approachfor this problem, using “targets” located in the external patchelectrode.

U.S. Pat. No. 5,269,303 (Wernicke) is directed to the use of pacemakertechnology (an implantable pulse generator) for the treatment ofdementia. The pacemaker technology concept consists of a stimulatinglead which is connected to a pulse generator (containing the circuityand DC power source) implanted subcutaneously or submuscularly,somewhere in the pectoral or axillary region, with a personal computer(PC) based programmer being external. Once the patient is programmed,the fully functional circuity and power source being fully implantedwithin the patients body. In such a system when the battery is depleted,the whole pulse generator (circuitry and power source) is disconnectedfrom the permanently implanted lead and replaced in a surgicalprocedure. This patent neither anticipates practical problems of aninductively coupled system for adjunct therapy of dementia, nor suggestsolutions to the same for an inductively coupled system for adjuncttherapy of dementia.

U.S. Pat. No. 4,867,164 (Zabara) generally discloses animal research andexperimentation related to epilepsy and the like, and use of pacemakertechnology (an implantable pulse generator) for the stimulation of vagusnerve. Some of the key hypothesis on which the patent is based upon,have since been shown to be incorrect.

U.S. Pat. No. 5,540,734 (Zabara) is directed to stimulation of one orboth of a patient's trigeminal and glossopharyngeal nerve utilizing animplanted pulse generator.

U.S. Pat. No. 5,031,618 (Mullett) discloses a position sensor forchronically implanted neuro stimulator for stimulating the spinal cord.The position sensor, located in a chronically implanted programmablespinal cord stimulator, modulates the stimulation signals depending onwhether the patient is erect or supine.

U.S. Pat. No. 4,573,481 (Bullara) is directed to an implantable helicalelectrode assembly configured to fit around a nerve. The individualflexible ribbon electrodes are each partially embedded in a portion ofthe peripheral surface of a helically formed dielectric support matrix.

U.S. Pat. No. 3,760,812 (Timm et al.) discloses nerve stimulationelectrodes that include a pair of parallel spaced apart helically woundconductors maintained in this configuration.

U.S. Pat. No. 4,979,511 (Terry) discloses a flexible, helical electrodestructure with an improved connector for attaching the lead wires to thenerve bundle to minimize damage.

An implantable pulse generator and lead with a PC based externalprogrammer is advantageous for cardiac pacing applications for severalreasons, including:

1) A cardiac pacemaker needs to sense the intrinsic activity of theheart, because in vast majority of instances, the cardiac pacemakersdeliver electrical output only during the brief periods when patientseither have pauses in their intrinsic cardiac activity or during thoseperiods of time when the heart rate drops (bradycardia) below a certainpre-programmed level. Therefore, for most of the time, in majority ofpatients, the cardiac pacemaker “sits” quietly monitoring the patient'sintrinsic cardiac activity.

2) The stimulation frequency for cardiac pacing is typically close to 1Hz as opposed to approximately 20 Hz or higher, typically used in nervestimulation applications.

3) Majority of patients that require cardiac pacemaker support aretypically in 60's, 70's or 80's years in age.

The combined effect of these three factors is that the pacemaker canhave a battery life of 10-15 years, and for most patients in whom apacemaker is indicated are implanted only once, with perhaps onesurgical pulse generator replacement.

For nerve stimulation applications, the stimulation frequency istypically 20 Hz or higher, and the total stimulation time per day ismuch longer, which results in battery expenditure that is typically muchhigher than for cardiac pacemakers, and the battery will not last nearlyas long. The impact of surgical generator replacement and expense willbecome significant, and detract from the appeal of this therapy. Thereare several other advantages of the present inductively coupled systemas set forth below,

1) The hardware components implanted in the body are much less. This isadvantageous for the patient in terms of patient comfort, and itdecreases the chances of the hardware getting infected in the body.Typically, when an implantable system gets infected in the body, itcannot be easily treated with antibiotics and eventually the wholeimplanted system has to be explanted.

2) Because the power source is external, the physician can usestimulation sequences that are more effective and more demanding on thepower supply such as longer “on” time.

3) The external inductively-coupled nerve stimulation (EINS) system isquicker and easier to implant.

4) The external pulse generator does not need to be monitored for“End-of-Life” EOL like the implantable system, thus resulting in costsaving and convenience.

5) The inductively-coupled nerve stimulation (EINS) system can bemanufactured at a significantly lower cost than an implantable pulsegenerator and programmer system, providing the patient and medicalestablishment with cost effective therapies.

6) The EINS system makes it more convenient for the patient or caretakerto turn the device on.

7) Occasionally, an individual responds adversely to a medical deviceand the implanted hardware must be removed. In such a case, a patienthaving the EINS system has less implanted hardware to be removed and thecost of pulse generator does not become a factor.

In the conventional manner of implanting, a cervical incision is madeabove the clavicle, and another infraclavicular incision is made in thedeltapectoral region for the implantable stimulus generator pocket. Totunnel the lead to the cervical incision, a shunt-passing tool is passedfrom the cervical incision to the generator pocket, where the electrodeis attached to the shunt-passing tool and the electrode is then “pulled”back to the cervical incision for attachment to the nerve. This standardtechnique has the disadvantage that it is time consuming and it tends tocreate an open space in the subcutaneous tissue. Post surgically thebody will fill up this space with serous fluid, which can beundesirable.

To make the subcutaneous tunneling simpler and to avoid possiblecomplication, one form of the implantable lead body is designed with ahollow lumen to aid in implanting. In this embodiment, a specialtunneling tool slides into a hollow lumen. After the cervical andinfraclavicular incisions are made, the tunneling tool and lead aresimply “pushed” to the cervical incision and the tunneling tool ispulled out. Since the tunneling tool is inside the lead, no extrasubcutaneous space is created around the lead, as the lead is pushed.This promotes better healing post-surgically.

The apparatus and methods disclosed herein also may be appropriate forthe treatment of other conditions, as disclosed in applications filed onOct. 26, 1998 entitled APPARATUS AND METHOD FOR ADJUNCT (ADD-ON) THERAPYOF PARTIAL COMPLEX EPILEPSY, GENERALIZED EPILEPSY AND INVOLUNTARYMOVEMENT DISORDERS UTILIZING AN EXTERNAL STIMULATOR and APPARATUS ANDMETHOD FOR ADJUNCT (ADD-ON) THERAPY FOR PAIN SYNDROMES UTILIZING ANIMPLANTABLE LEAD AND AN EXTERNAL STIMULATOR, the disclosures of whichare incorporated herein by reference. Now U.S. Pat. Nos. 6,205,359 B1,and 6,208,902 B1 respectively.

SUMMARY OF THE INVENTION

The apparatus and methodology of this invention generally relates to thetreatment of Dementia including probable Alzheimer's disease viaafferent stimulation using an implantable lead and a stimulator outsidethe body. In one embodiment of the invention, the apparatus consists ofan easy to implant lead-receiver, an external stimulator containingcontrolling circuitry and power supply, and electrode containing coilfor inductively coupling the external pulse generator to the implantedlead-receiver. A separately provided tunneling tool may be used as anaid for implanting the lead-receiver.

In another embodiment of the invention, the implantable lead-receiver isinductively coupled to the external stimulator via a patch electrodecontaining coil. One feature of this invention is to consistentlydeliver energy from an external coil to an internal coil in anambulatory patient. A design of the external patch contains means forcompensating for relative movement of the axis of the external andinternal coils by deflecting the energy via targets located in theexternal patch.

Another feature of this invention is to provide an apparatus to aid inimplanting the lead-receiver, including a hollow lumen in the lead bodyto receive a tunneling tool.

BRIEF DESCRIPTION OF THE DRAWINGS

For the purpose of illustrating the invention, there are shown inaccompanying drawing forms which are presently preferred, it beingunderstood that the invention is not intended to be limited to theprecise arrangement and instrumentalities shown.

FIG. 1A is a diagram of vagal nerve afferents through the nucleus of thesolitary tract.

FIG. 1B is a diagram showing a patient wearing an externalinductively-coupled nerve stimulator (EINS) system.

FIG. 2 is a diagram showing two coils along their axis, in aconfiguration such that the mutual inductance would be maximum.

FIG. 3A is a diagram showing the effects of two coils with axes at rightangles.

FIG. 3B is a diagram showing the effects of two coils with axes at rightangles, with a ferrite target included.

FIG. 4A is a side view of an external patch showing the transmittingcoil and targets.

FIG. 4B is top view of an external patch showing the transmitting coiland targets.

FIG. 5 is a diagram showing the implanted lead-receiver and thetransmitting coil.

FIG. 6 is a diagram showing the implanted lead-receiver underneath theskin, also showing the relative position of the external coil

FIG. 7 is a diagram showing the proximal end of the lead-receiver.

FIG. 8 is a diagram of circuitry within the proximal portion of theimplanted lead-receiver.

FIG. 9 is a diagram of the body of the lead-receiver.

FIG. 10 is a diagram of a tunneling tool for aiding in the implantationof the lead-receiver.

FIG. 11 is a diagram of another tunneling tool for aiding in theimplantation of the lead-receiver

FIG. 12 is a diagram of an external patch and external pulse generator.

FIG. 13 is a prospective view of an external pulse generator.

FIG. 14 is a flow diagram of the external pulse generator.

FIG. 15 is a diagram of a hydrogel electrode.

FIG. 16 is a diagram of a lead-receiver utilizing a fiber electrode atthe distal end.

FIG. 17 is a diagram of a fiber electrode wrapped around Dacronpolyester.

FIG. 18 is a diagram of a lead-receiver with a spiral electrode.

FIG. 19 is a diagram of an electrode embedded in tissue.

FIG. 20 is a diagram of an electrode containing steroid drug inside.

FIG. 21 is a diagram of an electrode containing steroid drug in asilicone collar at the base of electrode.

FIG. 22 is a diagram of an electrode with steroid drug coated on thesurface of the electrode.

FIG. 23 is a diagram of cross sections of implantable lead-receiver bodyshowing different lumens.

THE FOLLOWING ARE REFERENCE NUMBERS IN THE DRAWING

32. patient

34. implantable lead-receiver

36. coil-end of the external patch

38. wire of external patch

40. terminal end of the external patch

42. external stimulator

43. external patch electrode

44. belt of external stimulator

45. ferrite target

46. outer (transmitting) coil

48. inner (receiving) coil

49. proximal end of lead-receiver

50. adhesive portion of external patch electrode

51. driving voltage of transmitter coil

52. distal ball electrode

53. zero voltage of receiver coil

54. vagus nerve

55. signal voltage across receiver coil

56. carotid artery

57. ferrite targets in external patch

58. jugular vein

59. body of lead-receiver

60. working lumen of lead-receiver body

62. low lumen of lead-receiver body

64. schematic of lead-receiver circuitry

65. cable connecting cathode and anode

68. tuning capacitor in electrical schematic and in hybrid

70. zenor diode

71. pre-determined programs in block diagram

72. capacitor used in filtering

74. resister used in filtering

75. programmable control logic in block diagram

76. capacitor to block DC component to distal electrode

77. programming station in block diagram

78. case of lead-receiver

79. pulse frequency oscillator in block diagram

80. distal electrode in schematic of lead-receiver

81. battery (DC) in block diagram

82. working lumen in a cross section

83. amplifier in block diagram

84. hollow lumen in a cross-section

85. indicator in block diagram

86. small handle of alternate tunneling tool

87. low pass filter in block diagram

88. big handle of the tunneling tool

89. antenna in block diagram

90. skin

91. metal rod portion of the tunneling tool with big handle

92. punched holes in body of the lead receiver to promote fibrosis

93. metal rod portion of the alternative tunneling tool with smallhandle

94. alternative tunneling tool

95. tunneling tool with big handle

96. silicone covering proximal end

98. hybrid assembly

100. hydrogel

102. platinum electrodes around hydrogel

104. fiber electrode

105. spiral electrode

106. Dacron polyester or Polyimide

108. platinum fiber

110. exposed electrode portion of spiral electrode

112. polyurethane or silicone insulation in spiral electrode

114. “virtual” electrode

118. excitable tissue

120. non-excitable tissue

121. steroid plug inside an electrode

122. body of electrode

124. electrode tip

126. silicone collar containing steroid

128. steroid membrane coating

130. anchoring sleeve

132A-F lumens

134A-C larger hollow lumen for lead introduction

DETAILED DESCRIPTION OF THE INVENTION

FIG. 1B shows a schematic diagram of a patient 32 with an implantablelead-receiver 34 and an external stimulator 42, clipped on to a belt 44in this case. The external stimulator 42, may alternatively be placed ina pocket or other carrying device. An external patch electrode 36provides the coupling between the external stimulator 42 and theimplantable lead-receiver 34.

The external stimulator 42 is inductively coupled to the lead-receiver34. As shown in FIG. 2, when two coils are arranged with their axes onthe same line, current sent through coil 46 creates a magnetic fieldthat cuts coil 48 which is placed subcutaneously. Consequently, avoltage will be induced in coil 48 whenever the field strength of coil46 is changing. This induced voltage is similar to the voltage ofself-induction but since it appears in the second coil because ofcurrent flowing in the first, it is a mutual effect and results from themutual inductance between the two coils. Since these two coils arecoupled, the degree of coupling depends upon the physical spacingbetween the coils and how they are placed with respect to each other.Maximum coupling exists when they have a common axis and are as closetogether as possible. The coupling is least when the coils are far apartor are placed so their axes are at right angles. As shown in FIG. 5, thecoil 48 inside the lead-receiver 34 is approximately along the same axisas the coil 46 in the external skin patch 36.

As shown in FIG. 3A, when the axis of transmitting coil 46 is at rightangles to the axis of the receiving coil 48, a given driving voltage 51results in zero voltage 53 across the receiving coil 48. But, as shownin FIG. 3B by adding ferrite target 45, a given driving voltage 51through the transmitting coil 46 results in a signal voltage 55 acrossthe receiver coil 48. The efficiency is improved by having multipleferrite targets. An alternate external patch shown in FIGS. 4A and 4Bcontains multiple targets 57. FIG. 4A shows a side view of the patch,and FIG. 4B shows a top view of the patch. Having multiple targets 57 inthe external patch 43 compensates for non-alignment of the axis betweenthe transmitting coil 46 and receiving coil 48. Since relative rotationsbetween the axis of external transmitting coil 46 and internal receivingcoil 48 which may occur during breathing, muscle contractions, or otherartifacts are compensated for, results in continuous prolongedstimulation.

Referring to FIG. 6, the implantable lead-receiver 34 looks somewhatlike a golf “tee” and is the only implantable portion of the system. The“head” or proximal end 49 contains the coil 48 and electronic circuitry(hybrid) 98 which is hermetically sealed, and covered with silicone. Italso has four anchoring sleeves 130 for tying it to subcutaneous tissue.FIG. 7 is a close-up view of the proximal portion 49 of thelead-receiver 34 containing the circuitry (hybrid) 98. This circuitry isshown schematically in FIG. 8. A coil 48 (preferably approximately 15turns) is directly connected to the case 78. The external stimulator 42and external patch 36 transmit the pulsed alternating magnetic field toreceiver 64 whereat the stimulus pulses are detected by coil 48 andtransmitted to the stimulus site (vagus nerve 54 ). When exposed to themagnetic field of transmitter 36, coil 48 converts the changing magneticfield into corresponding voltages with alternating polarity between thecoil ends. A capacitor 68 is used to tune coil 48 to the high-frequencyof the transmitter 36. The capacitor 68 increases the sensitivity andthe selectivity of the receiver 64, which is made sensitive tofrequencies near the resonant frequency of the tuned circuit and lesssensitive to frequencies away from the resonant frequency. A zenor diode70 in the current path is used for regulation and to allow the currentthat is produced by the alternating voltage of the coil to pass in onedirection only. A capacitor 72 and resistor 74 filter-out thehigh-frequency component of the receiver signal and thereby leave acurrent of the same duration as the burst of the high-frequency signal.Capacitor 76 blocks any net direct current to the stimulating electrodetip 80, which is made of platinum/iridium (90%-10%). Alternatively, thestimulating electrode can be made of platinum or platinum/iridium inratio's such as 80% Platinum and 20% Iridium.

The circuit components are soldered in a conventional manner to an upperconductive layer on a printed circuit board. The case 78 is connected tothe coil 48 and is made of Titanium. The case 78 also serves as thereturn electrode (anode). The surface area of the anode exposed to thetissue is much greater than the surface area of the stimulatingelectrode 80 (cathode). Therefore, the current density at the anode istoo low to unduly stimulate tissue that is in contact with the anode.

The body of the lead-receiver 34 is made of medical grade silicone(available from NuSil Technology, Applied silicone or Dow Chemical).Alternatively, the lead body 59 may be made of medical gradepolyurethane (PU) of 55D or higher durometer, such as available from DowChemical. Polyurethane is a stiffer material than silicone. Even thoughsilicone is a softer material, which is favorable, it is also a weakermaterial than PU. Therefore, silicone coated with Teflon (PTFE) ispreferred for this application. PTFE coating is available from AlpaFlex, Indianapolis, Ind.

FIG. 9 shows a close-up of the lead body 59 showing two lumens 82, 84.Lumen 82 is the “working” lumen, containing the cable conductor 65 whichconnects to the stimulating electrode 52. The other lumen 84 ispreferably slightly larger and is for introducing and placing the leadin the body. Alternatively, lumen 84 may have small holes 92 punchedalong the length of the lead. These small holes 92 will promote fibrotictissue in-growth to stabilize the lead position and inhibit the leadfrom migrating.

Silicone in general is not a very slippery material, having a highcoefficient of friction. Therefore, a lubricious coating is added to thebody of the lead. Such lubricous coating is available from CoatingTechnologies Inc. (Scotch Plains, N.J.). Since infection still remains aproblem in a small percentage of patients, the lead may be coated withantimicrobial coating such as Silver Sulfer Dizene available from STSBiopolymers, Henrietta, N.Y. The lead may also be coated withanti-inflammatory coating.

The distal ball electrode 52, shown in FIG. 6 is made ofplatinum/iridium (90% platinum and 10% iridium). Platinum/iridiumelectrodes have a long history in cardiac pacing applications. Duringthe distal assembly procedure, the silicone lead body 59 is firstcleaned with alcohol. The conductor cable 65 (available from LakeRegion, Minn.) is passed through the “working” lumen 82. The cable isinserted into the distal electrode 52, and part of the body of electrodeis crimped to the cable 65 with a crimper. Alternatively, the cableconductor 65 may be arc welded or laser welded to the distal electrode52. The distal end of the insulation is then slided over the crimp suchthat only the tissue stimulating portion of the distal electrode 52 isexposed. Following this, a small needle is attached to a syringe filledwith medical glue. The needle is inserted into the distal end ofinsulation, and small amounts of medical glue are injected between thedistal end of the insulation and distal electrode 52. The assembly isthen cured in an oven.

As shown in FIGS. 9 and 10, a tunneling tool 95 is inserted into theempty lumen 84 to push the distal end (containing the cathode electrode52 ) towards the vagus nerve 54. The tunneling tool 95, is comprised ofa metal rod 91 and a handle 88. As shown in FIG. 11, another tunnelingtool 94 with a smaller handle 86 may also be used. Both are availablefrom Popper and Sons, New Hyde Park, N.Y. or Needle Technology.Alternatively, the tunneling tool may be made of strong plastic or othersuitable material.

An external patch electrode 43 for inductive coupling is shown in FIG.12. One end of the patch electrode contains the coil 46, and the otherend has an adapter 40 to fit into the external stimulator 42. Theexternal patch electrode 43, is a modification of the patch electrodeavailable from TruMed Technologies, Burnsville, Minn.

FIG. 13 shows a sketch of the external stimulator 42, which preferablyis slightly larger than a conventional pager. The external stimulator 42contains the circuitry and rechargeable power source. There are several(approximately up to 9) pre-packaged programs, which differ in stimulusintensity, pulse width, frequency of stimulation, and on-off timingsequence, e.g. “on” for 10 seconds and “off” for 50 seconds in constantrepeating cycles, for a given period of time. For patient safety anynumber of these programs may be locked-out by the manufacturer orphysician. When the device is turned on, a green light emitting diode(LED) indicates that the device is emitting electrical stimulation. Thefollowing are examples of possible pre-determined programs.

Program #1: 2.5 mA constant current, 40 μs pulses, applied in bursts oftrains, 10 pulses per train, with an internal frequency of 160 Hz, arepetition rate of 2 Hz applied for 30 minutes.

Program #2: 2.0 mA constant current, 40 μs pulses, applied in bursts oftrains, 12 pulses per train, with an internal frequency of 160 Hz, arepetition rate of 2 Hz with ON time-10 sec and OFF time 10 sec, appliedfor 60 minutes.

Program #3: 3.0 mA constant current, 40 μs pulses, applied in bursts oftrains, 8 pulses per train, with an internal frequency of 160 Hz, arepetition rate of 2 Hz with ON time 10 sec and OFF time 20 sec, appliedfor 120 minutes.

The above are examples of the pre-determined programs. The actualparameter settings for any given patient may deviate somewhat from theabove.

FIG. 14 is a top-level block diagram of the external stimulator 42.There are a series of (up to 9) pre-packaged programs 71, differing inthe aggressiveness of the therapy. The standard programs feed into theprogrammable control logic 75. The programmable control logic 75controls the pulse frequency oscillator 79 which sends appropriatepulses to the amplifier 83. From the amplifier 83, the signals gothrough a low pass filter 87 and to the antenna 89. The programmablecontrol logic 75 also feeds into an indicator 85 showing on-off status,as well as the battery status. The external stimulator 42 is powered bya DC battery 81. A programming station 77 provides the capability todownload and change programs if the need arises.

Conventional integrated circuits are used for the logic, control andtiming circuits. Conventional bipolar transistors are used inradio-frequency oscillator, pulse amplitude ramp control and poweramplifier. A standard voltage regulator is used in low-voltage detector.The hardware and software to deliver these predetermined programs iswell known to those skilled in the art.

The fabrication of the lead-receiver 34 is designed to be modular. Thus,several different components can be mixed and matched without alteringthe functionality of the device significantly. As shown in FIG. 6, thelead-receiver 34 components are the proximal end 49 (containing coil 48,electrical circuitry 98, and case 78 ), the lead body 59 containing theconductor 65, and the distal electrode (cathode) 52. In the modulardesign concept, several design variables are possible, as shown in thetable below.

Table of lead-receiver design variables Proximal End Circuitry ConductorDistal and Lead Lead body- (connecting End Return body- Insulation Lead-proximal and Electrode - Electrode - electrode Lumens materials Coatingdistal ends) Material Type Single Polyurethane Lubricious Alloy of PureStandard ball (PVP) Nickal—Cobalt Platinum electrode Double SiliconeAntimicrobial Platinum— Hydrogel Iridium electrode (Pt/Ir) alloy TripleSilicone with Anti- Pt/Ir coated Spiral Polytetrafluor inflammatory withelectrode oethylelne Titanium (PTFE) Nitride Coaxial Carbon Steroideluting Fiber electrode

Either silicone or polyurethane is suitable material for thisimplantable lead body 59. Both materials have proven to have desirablequalities, which are not available in the other. Permanently implantablepacemaker leads made of polyurethane are susceptible to some forms ofdegradation over time. The identified mechanisms are EnvironmentalStress Cracking (ESC) and Metal Ion Oxidation (NIO). For this reasonsilicone material is slightly preferred over polyurethane.

Nerve-electrode interaction is an integral part of the stimulationsystem. As a practical benefit of modular design, any type of electrodedescribed below can be used as the distal (cathode) stimulatingelectrode, without changing fabrication methodology or proceduresignificantly. When a standard ball electrode made of platinum orplatinum/iridium is placed next to the nerve, and secured in place, itpromotes an inflammatory response that leads to a thin fibrotic sheatharound the electrode over a period of 1 to 6 weeks. This in turn leadsto a stable position of electrode relative to the nerve, and a stableelectrode-tissue interface, resulting in reliable stimulation of thenerve chronically without damaging the nerve.

Alternatively, other electrode forms that are non-traumatic to the nervesuch as hydrogel, platinum fiber, or steroid elution electrodes may beused with this system. The concept of hydrogel electrode for nervestimulation is shown schematically in FIG. 15. The hydrogel material 100is wrapped around the nerve 54, with tiny platinum electrodes 102 beingpulled back from nerve. Over a period of time in the body, the hydrogelmaterial 100 will undergo degradation and there will be fibrotic tissuebuildup. Because of the softness of the hydrogel material 100, theseelectrodes are non-traumatic to the nerve.

The concept of platinum fiber electrodes is shown schematically in FIG.16. The distal fiber electrode 104 attached to the lead-receiver 34 maybe platinum fiber or cable, or the electrode may be thin platinum fiberwrapped around Dacron polyester or Polyimide 106. As shown in FIG. 17,the platinum fibers 108 may be woven around Dacron polyester fiber 106or platinum fibers 108 may be braided. At implant, the fiber electrode104 is loosely wrapped around the surgically isolated nerve, then tiedloosely so as not to constrict the nerve or put pressure on the nerve.As a further extension, the fiber electrode may be incorporated into aspiral electrode 105 as is shown schematically in FIG. 18. The fiberelectrode 110 is on the inner side of polyurethane or siliconeinsulation 112 which is heat treated to retain its spiral shape.

Alternatively, steroid elution electrodes may be used. Afterimplantation of a lead in the body, during the first few weeks there isbuildup of fibrotic tissue in-growth over the electrode and to someextent around the lead body. This fibrosis is the end result of body'sinflammatory response process which begins soon after the device isimplanted. The fibrotic tissue sheath has the net effect of increasingthe distance between the stimulation electrode (cathode) and theexcitable tissue, which is the vagal nerve in this case. This is shownschematically in FIG. 19, where electrode 52 when covered with fibrotictissue becomes the “virtual” electrode 114. Non-excitable tissue isdepicted as 120 and excitable tissue as 118. A small amount ofcorticosteroid, dexamethasone sodium phosphate commonly referred to as“steroid” or “dexamethasone” placed inside or around the electrode, hassignificant beneficial effect on the current or energy threshold, i.e.the amount of energy required to stimulate the excitable tissue. This iswell known to those familiar in the art, as there is a long history ofsteroid elution leads in cardiac pacing application. It takes only about1 mg of dexamethasone to produce the desirable effects. Three separateways of delivering the steroid drug to the electrode nerve-tissueinterface are being disclosed here. Dexamethasone can be placed insidean electrode with microholes, it can be placed adjacent to the electrodein a silicone collar, or it can be coated on the electrode itself.

Dexamethasone inside the stimulating electrode is shown schematically inFIG. 20. A silicone core that is impregnated with a small quantity ofdexamethasone 121, is incorporated inside the electrode. The electrodetip is depicted as 124 and electrode body as 122. Once the lead isimplanted in the body, the steroid 121 elutes out through the smallholes in the electrode. The steroid drug then has anti-inflammatoryaction at the electrode tissue interface, which leads to a much thinnerfibrotic tissue capsule.

Another way of having a steroid eluting nerve stimulating electrode, isto have the steroid agent placed outside the distal electrode 52 in asilicone collar 126. This is shown schematically in FIG. 21.Approximately 1 mg of dexamethasone is contained in a silicone collar126, at the base of the distal electrode 52. With such a method, thesteroid drug elutes around the electrode 52 in a similar fashion andwith similar pharmacokinetic properties, as with the steroid drug beinginside the electrode.

Another method of steroid elution for nerve stimulation electrodes is bycoating of steroid on the outside (exposed) surface area of theelectrode. This is shown schematically in FIG. 22. Nafion is used as thecoating matrix. Steroid membrane coating on the outside of the electrodeis depicted as 128. The advantages of this method are that it can easilybe applied to any electrode, fast and easy manufacturing, and it is costeffective. With this method, the rate of steroid delivery can becontrolled by the level of sulfonation.

A schematic representation of the cross section of different possiblelumens is shown in FIG. 23. The lead body 59 can have one, two, or threelumens for conducting cable, with or without a hollow lumen. In thecross sections, 132A-F represents lumens(s) for conducting cable and134A-C represents hollow lumen for aid in implanting the lead.

Additionally, different classes of coating may be applied to theimplantable lead-receiver 34 after fabrication. These coatings fall intothree categories, lubricious coating, antimicrobial coating, andanti-inflammatory coating.

The advantage of modular fabrication is that with one technologyplatform, several derivative products or models can be manufactured. Asa specific practical example, using a silicone lead body platform, threeseparate derivative or lead models can be manufactured by using threedifferent electrodes such as standard electrode, steroid electrode orspiral electrode. This is made possible by designing the fabricationsteps such that the distal electrodes are assembled at the end, and aslong as the electrodes are mated to the insulation and conducting cable,the shape or type of electrode does not matter. Similarly, differentmodels can be produced by taking a finished lead and then coating itwith lubricious coating or antimicrobial coating. In fact, consideringthe design variables disclosed in table 1, a large number ofcombinations are possible. Of these large number of possiblecombinations, about 6 or 7 models are planned for manufacturing. Theseinclude lead body composed of silicone and PTFE with standard ballelectrodes made of platinum/iridium alloy, and silicone lead body withspiral electrode.

While various embodiments of the present invention have been describedin detail, it is apparent that modifications and adaptations of thoseembodiments will occur to those skilled in the art. However, it is to beexpressly understood that such modifications and adaptations are withinthe spirit and scope of the present invention.

What is claimed is:
 1. An Alzheimer's disease and dementia therapyapparatus for providing pulsed electrical stimulation to a cranialnerve, comprising: a) an implantable lead-receiver comprising circuitry,a secondary coil, and least one electrode adapted to be in contact witha cranial nerve; b) an external stimulator comprising a power source,circuitry to emit electrical signals, more than two predeterminedprograms to control said electrical signals, and a primary coil; c) saidprimary coil of external stimulator and said secondary coil ofimplantable lead-receiver being capable of forming an electricalconnection by inductive coupling, whereby said external stimulatorcontrols said stimulation to said cranial nerve.
 2. The apparatus ofclaim 1, wherein said apparatus is adapted to stimulate a left vagusnerve.
 3. The apparatus of claim 1, wherein said external stimulatorfurther comprises patient override mechanism means to manually activatesaid external stimulator.
 4. The apparatus of claim 1, wherein saidexternal stimulator further comprises means to modify said more than twopredetermined programs.
 5. The apparatus of claim 1, wherein saidexternal stimulator further comprises means to selectively operate saidmore than two predetermined programs.
 6. The apparatus of claim 5,further comprising means to manually disengage said more than twopredetermined programs.
 7. The apparatus of claim 1, wherein saidelectrical signals comprise at least one variable component selectedfrom the group consisting of the current amplitude, pulse width,frequency and on-off timing sequence, and said more than twopredetermined programs controls said variable component of saidelectrical signals.
 8. The apparatus of claim 1, wherein saidlead-receiver further comprises a lead body with at least one lumen, alead body insulation, and a conductor.
 9. The apparatus of claim 8,wherein said lead body lumen is selected from the group consisting ofsingle, double, triple and coaxial lumens.
 10. The apparatus of claim 9,wherein said lead body insulation is selected from the group consistingof polyurethane, silicone and silicone with polytetrafluoroethylene. 11.The apparatus of claim 9, wherein said lead body further comprises acoating selected from the group consisting of lubricious PVP,antimicrobial and anti-inflammatory coatings.
 12. The apparatus of claim9, wherein said electrode comprises a material selected from the groupconsisting of platinum, platinum/iridium alloy, platinum/iridium alloycoated with titanium nitride and carbon.
 13. The apparatus of claim 1,wherein said electrode is selected from the group consisting of hydrogelelectrodes, spiral electrodes, steroid eluting electrodes, and fiberelectrodes.
 14. A dementia and Alzheimer's disease therapy apparatus forneuromodulating a cranial nerve, comprising: a) an implantablelead-receiver comprising circuitry, a secondary coil, and least oneelectrode adapted to be in contact with a cranial nerve; b) an externalstimulator comprising a power supply, circuitry to emit electricalsignals, more than two predetermined programs to control said electricalsignals, and a primary coil; c) means for optimizing coupling betweensaid primary coil and said secondary coil; d) said primary coil of saidexternal stimulator and said secondary coil of said implantablelead-receiver being capable of forming an electrical connection byinductive coupling, whereby said external stimulator neuromodulates saidcranial nerve.
 15. The apparatus of claim 14, wherein said apparatus isadapted to neuromodulate a left vagus nerve.
 16. The apparatus of claim14, wherein said external stimulator further comprises means for patientoverride mechanism to manually activate said external stimulator. 17.The apparatus of claim 14, wherein said external stimulator furthercomprises means for modifying said more than two predetermined programs.18. The apparatus of claim 14, wherein said external stimulator furthercomprises means to selectively operate said more than two predeterminedprograms.
 19. The apparatus of claim 18, further comprising means formanually disengaging said more than two predetermined programs.
 20. Theapparatus of claim 14, wherein said lead-receiver comprises a lead bodywith at least one lumen, a lead body insulation, and a conductor. 21.The apparatus of claim 20, wherein said at least one lumen is selectedfrom the group consisting of single, double, triple and coaxial lumens.22. The apparatus of claim 20, wherein said lead body insulation isselected from the group consisting of polyurethane,silicone and siliconewith polytetrafluoroethylene.
 23. The apparatus of claim 20, whereinsaid lead body further comprises a coating selected from the groupconsisting of lubricious PVP, antimicrobia and anti-inflammatorycoatings.
 24. The apparatus of claim 20, wherein said electrodecomprises a material selected from the group consisting of platinum,platinum/iridium alloy, platinum/iridium alloy coated with titaniumnitride and carbon.
 25. The apparatus of claim 14, wherein saidelectrode is selected from the group consisting of hydrogel electrodes,spiral electrodes, drug eluting electrodes, and fiber electrodes. 26.The apparatus of claim 14, wherein said electrical signals comprise atleast one variable component selected from the group consisting of thecurrent amplitude, pulse width, frequency and on-off timing sequence,and said more than two predetermined programs controls said variablecomponent of said electrical signals.
 27. An apparatus to providetherapy for Alzheimer's disease and dementia by providing pulsedelectric stimulation to a vagus nerve, comprising: a) an implantablelead-receiver comprising, circuitry, a secondary coil, and at least oneelectrode adapted to be in contact with a vagus nerve; b) an externalstimulator comprising a power supply, circuitry to emit electricalsignals, more than two predetermined programs to control said electricalsignals, and a primary coil; c) said primary coil of said externalstimulator and said secondary coil of said implantable lead-receiverbeing capable of forming an electrical connection by inductive coupling,whereby said external stimulator is capable of controlling saidstimulation to said vagus nerve.
 28. The apparatus of claim 27, whereinsaid vagus nerve is a left vagus nerve.